Central synaptic impairment persists in sensory and motor neurons that regenerate their peripheral axonal projections after nerve injury. New findings obtained in this grant period suggest that these impairments modify feedback about muscle length and motor activity and cause significant dysfunction of spinal circuits responsible for coordinating muscle activity. This proposal has two objectives in studying the central mechanisms that limit recovery of movement following nerve repair: (1) locate deficits within and imbalances between selected spinal circuits and (2) manipulate activity of afferents in attempt to restore the usefulness of sensory feedback. Experiments designed to meet the specific aims described below all involve electrophysiological study in vivo of adult rat?s months after a selected few muscle nerves are severed and surgically repaired. The physiological studies proposed here will be coordinated with morphological studies in Project 2 in order to enable function-structure interpretations.
Specific Aim 1 is motivated by findings obtained in this grant period which suggest the counterintuitive notion that inactivity of regenerated primary afferents promotes their recovery of synaptic transmission with motoneurons. Experiments will manipulate afferent activity in attempt to rescue central transmission of muscle-length feedback for those afferents which recover stretch sensitivity through peripheral regeneration.
Specific Aim 2 focuses on the recovery of recurrent feedback from motoneurons which is shown by Projects 1 and 2 to be incomplete despite successful regeneration of peripheral motor axons. Resultant modification of the spinal circuit receiving recurrent feedback will be probed in detail to test sites of dysfunction.
Specific Aim 3 will examine apparent imbalances in excitatory and inhibitory spinal circuits associated with dyscoordination of antagonist muscle activity. Meeting these aims will substantially advance this project's long-term goal of explaining the failure to regain normal central transmission from neurons that regenerate successfully in the periphery after nerve injury. These central impairments together with incomplete and misdirected regeneration in the periphery conspire to prevent nerve repair from restoring normal movement. By addressing the causes of deficits in purposeful movement, this project advances the mission of the NINDS to improve treatment of neurological disorders.

Public Health Relevance

When severed nerves regenerate they can restore the ability to move the affected arms and legs, but that movement is often less effective than normal. Studies proposed here will test a method for fixing some problems, and go on to discover the cause for other difficulties in coordinating movement.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS057228-07
Application #
8627652
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
7
Fiscal Year
2014
Total Cost
$418,304
Indirect Cost
$131,794
Name
Wright State University
Department
Type
DUNS #
047814256
City
Dayton
State
OH
Country
United States
Zip Code
45435
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Rotterman, Travis M; Nardelli, Paul; Cope, Timothy C et al. (2014) Normal distribution of VGLUT1 synapses on spinal motoneuron dendrites and their reorganization after nerve injury. J Neurosci 34:3475-92
Deardorff, Adam S; Romer, Shannon H; Sonner, Patrick M et al. (2014) Swimming against the tide: investigations of the C-bouton synapse. Front Neural Circuits 8:106
Romer, Shannon H; Dominguez, Kathleen M; Gelpi, Marc W et al. (2014) Redistribution of Kv2.1 ion channels on spinal motoneurons following peripheral nerve injury. Brain Res 1547:1-15
Zhang, Jingming; Lanuza, Guillermo M; Britz, Olivier et al. (2014) V1 and v2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion. Neuron 82:138-50
Koesters, Andrew; Engisch, Kathrin L; Rich, Mark M (2014) Decreased cardiac excitability secondary to reduction of sodium current may be a significant contributor to reduced contractility in a rat model of sepsis. Crit Care 18:R54
Deardorff, Adam S; Romer, Shannon H; Deng, Zhihui et al. (2013) Expression of postsynaptic Ca2+-activated K+ (SK) channels at C-bouton synapses in mammalian lumbar -motoneurons. J Physiol 591:875-97
Nardelli, Paul; Khan, Jaffar; Powers, Randall et al. (2013) Reduced motoneuron excitability in a rat model of sepsis. J Neurophysiol 109:1775-81
Wang, Xueyong; Wang, Qingbo; Yang, Shuzhang et al. (2011) Impaired activity-dependent plasticity of quantal amplitude at the neuromuscular junction of Rab3A deletion and Rab3A earlybird mutant mice. J Neurosci 31:3580-8
Bullinger, Katie L; Nardelli, Paul; Pinter, Martin J et al. (2011) Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. II. Loss of functional connectivity with motoneurons. J Neurophysiol 106:2471-85

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